Phenylbutyrate (PBA) is an oral analog of butyrate developed as a urea scavenger for rare metabolic diseases leading to elevated blood ammonia. PBA, by independent mechanisms, may increase gene expresion in other inherited disorders, particularly the hemoglobinopathies. We conducted the very first human trial for patients with cystic fibrosis (CF) who are homozygous for the most common CF mutation, the F508 mutation. This mutation encodes a full length gene product, which falls into the class of biosynthetic trafficking mutants, because it cannot move out of the endoplasmic reticulum. The F508 protein is a partially functional cAMP-regulated chloride channel in the nuclear-endoplasmic reticulum membrane and can be restrored to normal trafficking by reducing the temperature in cell culture to 27 degrees C. We studied primary and heterologous airway epithelial cells with this mutation in culture and demonstrated that PBA restores cAMP-activated chloride channels to the cell surface. The hypothesis in the clinical trial was that PBA would induce epithelial CF gene function in vivo in patients homozygous for F508. A randomized, double-blind, placebo-controlled trial in 18 patients 14 yrs and older was performed at the maximum FDA approved dose of 19 gm/day divided t.i.d. Sweat chloride and nasal potential difference patterns were measured before and after study drug. PBA and metabolites were measured in plasma and urine at the end of the study. Subjects in the PBA group demonstrated a statistically significant improvement, but not a completely normal, response in nasal potential difference after perfusion of isoproterenol in low chloride/amiloride solution. There was a linear correlation, r=0.54,p<0.05, between the isoproternol response and the plasma concentration of phenylacetate (major metabolite by beta oxidation of 4-PBA). Sweat chloride concentrations did not improved significantly during the study. We conclude that PBA therapy at 19 gm/day for 1 week induces partial CFTR function in nasal epithelia of patients expressing the F508 mutation. This approach has the potential of being a systemic treatment for cystic fibrosis.